Studies in patients with insulin dependent diabetes indicate that renal insufficiency develops following a long interval in which the glomerular filtration rate is elevated above normal. Like patients with early juvenile diabetes, rats given sufficient insulin to maintain moderate hyperglycemia exhibit elevation of the glomerular filtration rate. Micropuncture studies have shown that this elevation of glomerular filtration rate results from increases in glomerular capillary hydraulic pressure and plasma flow rate. Sustained increases in capillary pressure and flow have been associated with premature glomerular sclerosis in several models of renal disease. The objective of the current proposal is to examine the hypothesis that glomerular capillary hypertension and hyperperfusion also accelerate glomerular injury in diabetes. The first aim will be to identify factors which contribute to the altered glomerular hemodynamic function in diabetes. Micropuncture techniques will be used to assess glomerular function while agents which reduce angiotensin II, prostaglandin, and thromboxane A2 activity are infused and while renal perfusion pressure is lowered. The second aim will be to establish whether maneuvers that reduce glomerular capillary pressure and flow can repair the glomerular permselectivity defect responsible for proteinuria in diabetic nephropathy. Dextran fractional clearance profiles will be used to characterize glomerular membrane pore structure in diabetic rats with established proteinuria and to determine the effects of various pharmacologic agents on the membrane pore structure of the diabetic glomerular capillary wall. The third aim will be to determine whether agents which tend to normalize glomerular hemodynamic function and/or glomerular permselectivity can retard the development of glomerular sclerosis in experimental diabetes. The ultimate goal of these experimental studies is to provide a rational basis for treatment aimed at limiting glomerular injury in diabetes mellitus.